There is considerable interest in the cellular and molecular basis of memory formation. Studies of learning and memory are of fundamental importance for a better understanding of cognitive disorders in humans including Alzheimer's, autism, aging-related memory loss, and various types of mental retardation. It is the general hypothesis of this proposal that Ca2+ stimulation of the CREB/CRE (cAMP response element)-transcriptional pathway plays a pivotal role in long-lasting, long-term potentiation (L-LTP) and some forms of hippocampus-dependent long-term memory (LTM). Our long-term objectives are to define the mechanisms for Ca2+ stimulation of CRE-mediated transcription in hippocampal neurons and to understand why activation of this pathway is important for LTM and L-LTP. We hypothesize that Ca2+ activation of CRE-mediated transcription requires coactivation of the Erk/MAPK and camp signal transduction pathways. We propose that the critical cAMP signal increase originates from activation of calmodulin-stimulated adenylyl cyclases. We hypothesize that cAMP signaling is required for the nuclear translocation of Erk/MAPK and may also contribute to Ca2+ activation of Erk/MAPK. We also propose that proteolytic degradation of SCOP, a Ras inhibitor, may contribute to Ca2+ activation and sensitization of the Erk/MAPK signal transduction pathway. We hypothesize that long-lasting increases in CRE-mediated transcription, or transcriptional oscillations, in the hippocampus may be due to increased expression of gene products that function as positive-feedback regulators of the Erk/MAPK/CRE transcriptional pathway.